1. Field of the Invention
The present invention relates generally to medical implants and to methods for their use. More particularly, the present invention relates to preventing or inhibiting infections internal to the patient in the vicinity of subcutaneously implanted devices or associated with the use of such devices and to configurations of devices that prevent or alleviate localized internal infections. As used herein, the phrase xe2x80x9cinhibiting infectionxe2x80x9d and variations thereof refer both to prophylactic treatment to avoid infection and to therapeutic treatment to eliminate an established infection. More specifically, this invention relates to preventing or inhibiting infections in the vicinity of implanted hemodialysis ports.
2. Description of Related Art
Subcutaneously and transcutaneously implanted devices are utilized for a wide variety of purposes, e.g., drug infusion and hemodialysis access. Heart pacemakers have become commonplace. All such implanted devices are at some risk for infection.
The focus of interest for use of the current invention is hemodialysis access systems for access to human or animal patient""s vascular system for high fluid flow rate exchange of blood between the vascular system and an external processing apparatus Various improved access devices have been developed and described in numerous prior art documents.
Such a device is typically a subcutaneously implanted port connected to a blood vessel or other body lumen or cavity usually using a catheter. The port has an aperture for receiving a percutaneous access tube, e.g., a needle. Typical access port apparatuses are disclosed in U.S. Pat. Nos. 5,180,365; 5,226,879; 5,263,930; and 5,281,199.
Ports represent a significant advance over transcutaneous catheters and have a number of common fundamental design features. The ports themselves are made from a variety of materials, e.g., titanium, ceramics, and various plastic materials, e.g., polysulphone, and comprise a housing which forms a reservoir. A surface of the reservoir may be enclosed by a high-density, self-sealing septum, typically made of silicone rubber. Connected to the port housing is typically an implanted catheter that communicates with a vein or other site within the patient where the infusion of therapeutic agents is desired. Implantation of such devices generally proceeds by making a small subcutaneous pocket in an appropriate area of the patient under local anesthesia. The implanted catheter is tunneled to the desired infusion site. When the care provider desires to infuse or remove materials through the port, a hypodermic needle which pierces the skin over the infusion port and docks with the port is inserted.
Recently, improved devices of this class addressing these problems have been developed and described in U.S. Pat. No. 5,954,691 and U.S. patent application Ser. No. 09/083,078, filed May 21, 1998, the disclosures of which are incorporated herein by reference in their entirety. These inventions are directed to a hemodialysis access system for access to a human or animal patient""s vascular system for high fluid flow rate exchange of blood between the vascular system and an external processing apparatus at a volumetric flow rate in excess of 250 ml/minute.
Notwithstanding improvements in the construction of subcutaneous ports, problems still remain that retard their full usefulness in medical practice. Specifically, from time to time infections develop in the capsules or pockets surrounding the implanted devices. Such infections are difficult to treat for the reasons discussed herein and often require the removal of the port or other implanted device.
It is well known that a relatively hard tissue capsule or xe2x80x9cpocketxe2x80x9d usually forms around an artificial object or device implanted under the skin if the exterior surface of the device is impermeable to tissue in-growth, e.g., where the surface is both hard and non-porous. Pocket formation typically takes place within a few weeks of the implantation of the object in subcutaneous tissue. The capsule, approximately 1 mm thick, forms tightly around the implanted object. Such a capsule is usually white or pinkish and quite slippery to the touch on the inside. The outside of the capsule is attached to the patient""s normal subcutaneous tissue. The matrix of the capsule is normally without blood vessels or is very poorly vascularized. When the implanted device comprises a non-porous metal, plastic or elastomer, the capsule usually does not stick or adhere to the artificial material. To a large extent, but not completely, the pocket seals the implanted device off from the surrounding living tissue.
It is also known that infections of subcutaneously implanted ports arise most frequently from skin bacteria transported through the skin by needle penetration. Bacteria, having entered the space between the external surface of the device and the opposed tissue surface, can then attach to the port outer surface and grow into colonies in a layer or film form called biofilm.
While initially localized within the pocket formed around a device, such a colony may not cause symptoms or manifest as an infection for a long time. However, bacteria from the biofilm colony may shed and cross the pocket membrane, whereby an infection will manifest itself. Such an infection can become a local tissue infection indicated by local swelling, pus formation, local heating and pain, and so on, and it can also lead to systemic blood infection. These latter infections are very serious and if not treated often lead to morbidity and ultimately death.
One of the inventors herein, Dr. Sodemann, examined a surgical site at autopsy of a 79 year old patient who had an implanted hemodialysis port for approximately 6 months. There had been no incidents or symptoms which would have suggested an active infection at any time. After autopsy, however, it was found that the outer surface of the implant had been colonized with bacteria. It was concluded that bacteria had not propagated to surrounding tissue outside of the capsule and hence infection had not been suspected.
Infections near a subcutaneously implanted device have frequently been treated by systemic administration of antibiotics after somatic symptoms appear. Often such treatment does not work and the implanted device must be removed, subjecting the patient to additional trauma and leaving the patient without benefit of the device for the time it takes to clear the infection and replace the removed implant with another device. Moreover, the need to administer antibiotics frequently to patients is expensive and patients who suffer from repeated infections often develop strains of bacteria resistant to antibiotics.
Dr. Sodemann conducted a clinical study of a new port for hemodialysis patients, the Dialock(copyright), aided by a proprietary catheter lock solution to prevent infection and clotting inside the indwelling catheter. The method of using the proprietary antimicrobial locking solution in all patients for the first 14 months of the study was to instill the locking solution only in the catheter at the end of a dialysis session and discard it at the beginning of the next session. This study enrolled some 65 patients (the individual implant time ranged from a few weeks to 2 years) for an accumulated experience of approximately 60 patient-years. This study showed an overall infection rate of approximately 0.9 infection episodes per 1000 days of hemodialysis treatment using Dialock(copyright) as an access with the proprietary catheter locking solution. The breakdown was approximately 0.1 episodes per 1000 days for blood infections and 0.8 episodes per 1000 days for pocket infection. These infection results compare very favorably with results reported in review papers published in peer reviewed journals, namely, 2 to 10 episodes per 1000 days.
The inventors concluded from the foregoing observations that the risk of pocket infection remained problematic, however. Patients are at risk of having their tissue exposed to bacteria or fungi during each accessing procedure, which usually occurs 3 times a week for the remainder of the patient""s life unless the patient receives a successful transplant. Various skin infections abound in dialysis clinics. Studies show that 25-30% of patients and medical staff in hemodialysis clinics are carriers of common pathogens. Bacterial colonization of the surface of the implant inside the capsule has been observed, leading the inventors to conclude that the tissue capsule barrier shields bacteria on the implant surface from the patient""s immune system. Thus there is a need for a method of defeating infections around implants inside the tissue pocket.
In the first part of Dr. Sodemann""s clinical trial, a substantial number of enrolled patients developed pocket infections. Seven of these patients were treated in the normal manner, namely with systemic levels over a protracted time period of antibiotic specific to the identified bacterium causing the infection. This treatment uniformly failed to eradicate the infections and the implanted devices had to be surgically removed. Immediate removal is the recommended practice because it is very difficult to treat infection from a device that is colonized with a biofilm, and infection that remains in the body will over the long term lead to patient death. Such infections create a dilemma for the patient, who must lose access to renal replacement therapy, which is necessary to sustain the patient""s life. Consequently the patient needs to have an alternate access provided and often such patients have exhausted their access sites.
Not satisfied with this situation, Dr. Sodemann began treating his patients with pocket infections in a new way. These patients were systemically infused with antibiotic in the normal manner but were additionally treated with a local bolus of antibiotic at the site of the infection. Dr. Sodemann injected 1 ml of the specific antibiotic directly into the capsule space around the implant. In each of these 12 tissue infections the clinical signs of local infection quickly disappeared. These pocket infections were eradicated and did not reoccur. Thus tissue infections intractable to systemic antibiotic treatment were eradicated using local instillation of antibiotics directly into the inner space of the capsule.
Next it was thought that it might be possible to prevent pocket infections even before they occur. However, it was necessary to determine if one could store an antimicrobial solution within the capsule itself and slow down the normal transport of active ingredients into the circulation which occurs with subcutaneous injection or muscle injection. Accordingly, Dr. Sodemann began a safety experiments to see if a high quantity of antimicrobials could be stored within the capsule. The testing was conducted to determine whether a pathway existed for drug delivery from inside of the intact tissue capsule to the blood stream and the rate of any such drug delivery. He injected a normal loading dose of gentamicin (160 mg per 1 ml saline) into the capsule in patients with implanted access devices. Levels of gentamicin in the patient""s bloodstream were measured at 0, 1, 4, 12, 24, 48, and 72 hours after administration.
The measurements indicate a slow uptake in the blood, achieving a very low (non-pharmacologic) bloodstream dose maintained it at steady state over a few days. This means that the capsule is acting as a barrier to rapid uptake into the blood. This steady state level is maintained for a long time. Thus, it appears that the diffusion properties of the capsule acting as a permeable barrier govern the uptake rate. It also suggests that the drug stored inside the capsule does not degrade over the three day measurement period.
Based on these insights, a method was devised to prevent tissue infection. The proprietary catheter lock solution (CLS) is instilled into the catheter in the normal fashion and an additional amount of CLS is flowed into the space between the natural tissue capsule and the implant according to the following procedure.
Syringes were filled with a volume of catheter lock solution determined by the internal volume of the indwelling catheter plus 0.5 ml. After filling of the catheter, the needle was partially retracted so that the tip was resting at the entrance of the implant entrance passage. At this point the remaining 0.5 ml in the syringe was injected into the space at the entrance of the implant so that it flowed into the tissue capsule.
This technique has now been applied clinically for many months with 20 patients. The cumulative experience time is about 5000 days. No infection has occurred in patients to whom this technique was applied. Previous experience would suggest that one should expect about 5 infections. Accordingly, there is a clear desirability to incorporate antimicrobial substances in the pocket around the implanted device.
It is known that certain metals not toxic to the patient in small concentrations have an oligodynamic effect. (In general, oligodynamic denotes a substance for which very small amounts have a large effect. For the purposes of this application, oligodynamic means substances, such as, but not limited to, certain metals, which have a toxic effect on microbes such as bacteria and fungi in small amounts or at low concentrations.) U.S. Pat. No. 4,054,139 discloses a percutaneous catheter coated with an oligodynamic agent such as metallic silver or its compounds, alone or in association with other heavy metals, such as gold, for the purpose of reducing infection associated with these devices. The oligodynamic agent is typically applied to both interior and exterior surfaces of the disclosed catheters. In another example, U.S. Pat. No. 4,923,450 discloses percutaneous medical tubes having antibacterial action against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and fungus, achieved by means of anhydrous or crystallization-water-containing powdered zeolite, wherein one of the metals contained in said zeolite is substituted by Ag, Cu, or Zn, the zeolite being coated onto or kneaded into at least the portion of said tubes which indwells in the body of the patient. In another example, U.S. Pat. No. 5,295,979 discloses a urinary catheter with a drain lumen coated with oligodynamic metal and with an additional coating of a more noble metal for creating an iontophoretic galvanic couple, which drives antimicrobial ions into solution. The exterior of the catheter is also coated in a similar manner to inhibit microbes migrating toward the bladder along the outer surface of the catheter.
Other inventions use coating of plastics containing anti-infective substances to create infection barriers at crucial points on catheters which penetrate the skin. For example, U.S. Pat. No. 5,567,495 discloses primarily discs or rings that are anti-infective as a result of anti-infective agents impregnated in their surfaces and/or antiinfective activity incorporated into their access sites. The invention is based, at least in part, on the discovery that certain combinations of antimicrobial agents and solvents change the surface characteristics of polymeric medical devices, thereby facilitating the retention of antimicrobial agents. It is further based on the discovery that the incorporation of antiinfective polymeric inserts into the access site of a medical device provides substantially improved antiinfective activity. Similarly, U.S. Pat. No. 5,620,424 discloses an attachable device, for use with a catheter, and impregnated with, or containing, a supply of antiseptic solution, gel or powder, such that the device can be exteriorly positioned adjacent a catheter insertion site, thereby dispensing antiseptic solution at the catheterization site for preventing micro-organisms surrounding the insertion site from causing infection.
U.S. Pat. No. 5,685,961 discloses catheters and other medical devices that include application of multiple layers of metal. In some embodiments, the initial layer of material is silver applied following specific preparation steps. In other embodiments, succeeding layers of metal completely cover the initial layer, and are also of silver. The succeeding layers are deposited over the prior layer, and tend to reduce the incidence of microscopic pores or cracks and are less prone to delamination. The succeeding layers are preferably of mutually different metals between layers. In a particular embodiment, in which the exposed metals are oligodynamic silver and more noble platinum, the exposed silver layer lies over a portion of the platinum layer, to thereby prevent corrosion of the silver layer from disconnecting portions of the silver layer. Fabrication methods include deposition of successive layers by means of sputtering in a longitudinal array of cylindrical magnetron sections, in which each section applies one layer of the coating over the coating applied by the preceding section.
U.S. Pat. No. 5,688,516 discloses compositions and methods of employing them in flushing and coating medical devices. The compositions include selected combinations of a chelating agent, anticoagulant, or antithrombotic agent, with an non-glycopeptide antimicrobial agent, such as the tetracycline antibiotics. Methods of using these compositions for coating a medical device and for inhibiting catheter infection are also disclosed. Particular combinations of the identified substances include minocycline or other non-glycopeptide antimicrobial agent together with EDTA, EGTA, DTPA, TTH, heparin and/or hirudin in a pharmaceutically acceptable diluent. The use of silver sulfadiazine coatings as an antimicrobial agent is also described.
U.S. Pat. No. 5,718,694 discloses a method of inhibiting adherence of bacteria, fungus and other similar microorganisms to the surface of biomaterials, wherein biomaterials, such as catheters and prosthetic devices, are pretreated with a coating of a simple carbohydrate, such as a mono- or di-saccharide. Intravascular catheters treated as such are shown to have significant reduction of adherence by S. epidermidis, S. aureus, Candidas and other organisms associated with nosocomial infection.
In general these inventions are directed to preventing infections in patients using percutaneous catheters and other devices with permanent rather than transient skin penetration. In addition, these inventions are directed to disinfection of the lumens of such catheters. What is lacking in the prior art is a method of prophylaxis of infections specifically in a closed pocket surrounding an implanted device where there is no permanent penetration of the patient""s skin.
At least one patent publication, WO 99/34852, Brugger, et al. (Jul. 15, 1999) describes the infusion of an antimicrobial substance into the space surrounding an implanted device in order to defeat such infections before they become systemic. Brugger, et al. discloses implanted ports and other devices disinfected by the injection of an antimicrobial agent into a region in the device or in a tissue pocket surrounding the device. In a first embodiment, the antimicrobial agent is injected through an aperture in the device to flush internal regions of the device before infusing the tissue pocket, and flushing outwardly through a tissue tract leading to the device. In other embodiments, the antimicrobial agent is injected directly to a target site on the exterior of the device. Implanted devices may include special, usually hardened, target regions for receiving the sharpened end of a needle used to inject the antimicrobial agent. This method generally requires repeated dedicated injections.
It is therefore an object of the current invention to provide apparatus and method for disinfecting or providing infection prophylaxis with respect to indwelling devices with no permanent fluid connection to the exterior of the patient""s skin. It is a further object of this invention to provide means of disinfecting or providing infection prophylaxis of the exterior of implanted devices and the tissue pocket that typically forms around such a device. It is yet a further objective of this invention to provide a system for the use of non-antibiotic antimicrobial substances which do not cause the development of drug resistant strains of bacteria. It is a further objective to provide a system for pocket protection which is cooperative with a system for protecting the lumen of indwelling catheters from infection and clotting.
In accordance with the present invention, in one embodiment ports and other implantable devices, such as pacemakers and artificial joints, are provided having exterior surfaces comprising an antimicrobial material, whereby bacterial infection in the vicinity of the implanted port is reduced. More particularly, this embodiment is directed to an improved implantable port of the type including a housing that is implanted within a subcutaneous tissue pocket, wherein the improvement comprises the presence of metallic silver, an inorganic silver compound, or a silver salt of an organic acid on the surfaces of the port in contact with, or proximate to, the tissue of said pocket.
In another embodiment, the invention comprises a separate container in the form of a pouch substantially surrounding the implanted device intermediate between the device and the subcutaneous pocket. The pouch, which has anti-microbial properties, is slipped over the device before implantation so as to cover most of the implant surface.
A third embodiment comprises use of a reservoir or depot to hold either an antimicrobial solution or a slurry comprising particles of an antimicrobial substance with low solubility. In one subembodiment this substance can be taurolidine and related substances. In another silver metal or relatively insoluble silver salts may be used. A variation on this embodiment uses an implantable pump which can be periodically refilled.
In a fourth embodiment particularly relevant to hemodialysis, the procedure for withdrawal of the connecting needle is altered so that the needle is at first only partly withdrawn to a predetermined position, whereby a predetermined amount of catheter lock solution can be instilled into the pocket surrounding the device. In a highly preferred version of all of the foregoing, taurolidine or its close chemical relatives or mixtures thereof are used because they are known not to foster development of microbial resistance.